HMG-COA reductase inhibitors

ABSTRACT

Disclosed are novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors useful as antihypercholesterolemic agents represented by the formula ##STR1## and the corresponding ring-opened hydroxy acids derived therefrom and pharmaceutically acceptable salts thereof. 
     Pharmaceutical compositions containing said compounds and method of inhibiting the biosynthesis of cholesterol therewith are also disclosed.

This application is a division of application Ser. No. 283,111, filed onDec. 12, 1988, and issued on U.S. Pat. No. 4,904,692 which in turn is acontinuation-in-part of application Ser. No. 135,805, filed on Dec. 21,1987, and issued as U.S. Pat. No. 4,863,957.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds, pharmaceutical compositionsand a method useful for reducing serum cholesterol in humans. Moreparticularly, the invention relates to trans-6-[2-[aryl andarylalkylbicyclo[a.2.b]alk(en)yl]-alk(en)yl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran2-ones,the corresponding ring opened hydroxy acids derived therefrom andpharmaceutically acceptable salts thereof which are potent inhibitors ofthe enzyme 3-hydroxy-3methylglutaryl-coenzyme A reductase (hereinafterHMG-CoA reductase), pharmaceutical compositions thereof, and a method ofinhibiting biosynthesis of cholesterol for the treatment ofatherosclerosis, hyperlipidemia and hypercholesterolemia.

2. Related Prior Art

Inhibitors of HMG-CoA are effective in lowering blood plasma cholesterollevel as well as inhibiting the biosynthesis of cholesterol in humans.As such, inhibitors of HMG-CoA are useful in the prevention andtreatment of coronary heart diseases. The prior art recognizes theimportance of such compounds, e.g., Bethridge et al., Brit. Med. J.,4,500 (1975) and Brown et al., Scientific American, 58 Nov. (1984).Illustrative references directed to such compounds follow.

U.S. Pat. No. 4,681,893 to B. D. Roth pertains to trans-6-[2-(3-or4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-onesuseful as hypochloesterolemic agents.

U.S. Pat. No. 4,668,699 to Hoffman et al. discloses semi-syntheticanalogs of compactin and mevinolin and the dihydro and tetrahydroanalogs thereof for antihypercholesterolemic application.

U.S. Pat. No. 4,282,155 to Smith et al. is directed to6(R)-[2-(8'-Etherified-hydroxy-2', 6'-dimethylpolyhydronaphtyl-1']-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones for inhibition ofbiosynthesis of cholesterol.

U.S. Pat. No. 4,567,289 relates to methyl, ethyl, n-propyl,2-(acetylamino)ethyl, or 1-(2,3-dihydroxy)propyl ester ofE-(3R,5S)-7-(4,-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoicacid that are HMG-CoA reductase inhibitors.

U.S. Pat. No. 4,611,067 discloses a process for the preparation ofHMG-CoA reductase inhibitors which contain a4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety.

SUMMARY OF THE INVENTION

In accordance with the present invention, certain trans-6-[2-[aryl andarylalkylbicyclo[a.2.b]alk(en)yl]alk(en)yl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones,the corresponding ring-opened hydroxy-acids derived therefrom andpharmaceutically acceptable salts thereof are provided which are potentinhibitors of HMG-CoA reductase. Specifically, the invention providescompounds of the formula ##STR2## and pharmaceutically acceptable saltsthereof; wherein Y is:

--CHR--,

--CHRCHR--,

--CHRCHRCHR--, or

--RC═CR--;

X, X₁ and X₂ are independently:

H,

F,

Cl,

Br,

OH,

CF₃

alkyl,

alkoxy,

aryl,

NO₂,

NH(CO)R,

N(R)₂, or

S(O)_(n) R;

R, R₁, R₂, R₃ and R₄ are independently:

H or lower alkyl;

m is: 1 or 2;

m' is: 0 or 1;

m" is: 0 or 1;

n=0, 1, 2; and

the dotted lines in the bicyclic ring represent optional double bonds.

DETAILED DESCRIPTION OF THE INVENTION

As employed above and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeaning:

"Lower alkyl" means a saturated or unsaturated aliphatic hydrocarbonwhich may be either straight--or branched-chained containing from 1 to 4carbon atoms.

"Alkyl" means a saturated or unsaturated aliphatic hydrocarbon which maybe either straight-or branched-chained containing from about one toabout six carbon atoms.

"Alkoxy" means an alkyl oxy group in which "alkyl" is as previouslydefined. Lower alkoxy groups are preferred which include methoxy,ethoxy, n-propoxy, i-propoxy, sec-propoxy, and n-butoxy.

"Aryl" means an aromatic hydrocarbon radical having 6 to 10 carbonatoms. The preferred aryl groups are phenyl, substituted phenyl andnaphthyl. The term "substituted" means "alkyl" substitution.

The pharmaceutically acceptable salts of the present invention includethose formed from sodium, potassium, calcium, aluminum, lithium,magnesium, zinc, lysine, arginine, procaine, ethylenediamine andpiperazine.

The invention encompasses optical and stereoisomers of the compounds andmixtures thereof defined by the structural formula.

The general procedure for producing the compounds of the presentinvention is as follows:

Reaction Sequence

Reaction sequences A and B, corresponding with Examples 1 and 2respectively, illustrate the general methods for synthesizing thecompounds of the present invention. ##STR3##

The starting materials were obtained from the Aldrich Chemical Co. orthey may also be synthesized in accordance with methods known in theart.

The following preparative examples will further illustrate theinvention.

EXAMPLE 1 Step 1: Preparation of 3-(4-fluorophenyl)bicyclo[3.2.1]octane-2-spiro-(2'-oxirane)

To a solution of chloromethyl phenyl sulfoxide (3.70 g, 21.2 mmoles) inanhydrous tetrahydrofuran (THF) at -78° C. and under a N₂ atmosphere wasadded n-butyl lithium (8.5 ml of a 2.5M solution in hexane, 21.2 mmoles)dropwise. The solution was stirred for 10 minutes and a solution of2-(4-fluorophenyl)-l-oxobicyclo[3.2.1]octane (Tetrahedron Letters, 525327 (1967)) (4.40 g, 20.2 mmoles) in 20 ml THF was added. The solutionwas stirred for 60 minutes and diluted with ether and water. The organiclayer was washed with water, dilute aqueous HCl, saturated NaHCO₃ andbrine and dried (MgSO₄). Removal of the volatiles in vacuo provided aresidue which was treated with 100 ml of 20% KOH in methanol for 10minutes. The volatiles were removed in vacuo and the residue was dilutedwith ether and water. The organic layer was washed with water and brineand dried (MgSO₄). Removal of the volatiles in vacuo provided a residuewhich was recrystallized with hexanes in ethyl acetate and provided 5.38g of product. mp 178°-180° C.

Step 2: Preparation of3-(4-fluorophenyl)bicyclo[3.2.1]oct2-ene-2-carboxaldehyde

A solution of 3-(4-fluorophenyl)bicyclo[3.2.1]octane2-spiro-(2,-oxirane)(5.1 g) and 5.1 ml of BF₃ etherate in 50 ml CH₂ Cl₂ was stirred at 25°C. for 18 hours and diluted with ether and water. The organic layer waswashed with brine and dried (MgSO₄). Removal of the volatiles in vacuoprovided a residue which was purified by HPLC using 40/1 hexanes/ethylacetate as the eluent. Concentration in vacuo of the product richfractions provided the product as an orange oil.

Step 3: Preparation of3-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-propenal

To a 0°-5° C. solution of LDA (26.5 mmoles) in 25 ml anhydrous ether wasadded ethylidenecyclohexylamine (Org. Syn. 50 66) (3.32 g, 26.5 mmoles)in 25 ml anhydrous ether. The solution was stirred for 10 minutes,cooled to -70° C. and3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-ene-2-carboxaldehyde (5.55 g, 24.1mmoles) in 25 ml ether was added. The solution was stirred for 60minutes, warmed to 0°-5° C., stirred for 90 minutes and diluted withwater. The organic layer was washed with water and brine and dried(MgSO₄). Removal of the volatiles in vacuo provided a residue which waspurified by HPLC using 3% ethyl acetate in hexanes as the eluent.Concentration in vacuo of the product rich fractions provided 2.53 g ofthe product as an orange oil.

Step 4: Preparation of methyl (E)-7-[3-[4-fluorophenyl) bicyclo[3.2.1]oct-2-en-2-yl]-5-hydroxy-3-oxohept-6-enoate

To a 0°-5° C. suspension of pentane-washed sodium hydride (0.43 g, 10.6mmoles) in 10 ml anhydrous THF was added dropwise methyl acetoacetate.The solution was stirred for 30 minutes and n-butyl lithium (5.8 ml of a1.6M solution in hexanes, 9.31 mmoles) was added dropwise. The solutionwas stirred for 20 minutes and a solution of3-[3-(4-fluorophenyl)bicyclo [3.2.1]oct-2-en-2-yl]propenal (2.50 g, 9.75mmoles) in 15 ml anhydrous THF was added. The resulting solution wasstirred for 60 minutes and quenched with ether and aqueous HCl. Theorganic layer was washed with water and brine and dried (MgSO₄). Removalof the volatiles in vacuo provided 3.3 g of the solid product which wasused without further purification.

Step 5: Preparation of methyl (E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-3.5-dihydroxyhept-6-enoate

To a solution of methyl (E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-5-hydroxy-3-oxohept-6-enoate (2.85 g, 7.65 mmoles)in 12 ml anhydrous THF was added triethylborane (11.5 ml of a 1M THFsolution, 11.5 mmoles). The mixture was stirred for 5 minutes and cooledto -78° C. Sodium borohydride (0.333 g, 8.8 mmoles) was added followedby the dropwise addition of 5 ml methanol. The mixture was stirred for60 minutes and quenched with the dropwise addition of aqueous H₂ O₂ (12ml of 30% H₂ O₂ in 27 ml H₂ O). The mixture was warmed to 25° C. during90 minutes and poured into a mixture of ethyl acetate and aqueous HCl.The organic layer was washed with water and brine and dried (MgSO₄).Removal of the volatiles in vacuo provided a residue which was purifiedby HPLC using 60% hexanes in ethyl acetate. The product rich fractionswere concentrated in vacuo and provided 1.32 g of the oily product.

Step 6: Preparation of(E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-3,5-dihydroxyhept-6-enoicacid

A solution of methyl(E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-3,5-dihydroxy-hept-6-enoate(1.30 g, 3.47 mmoles) and aqueous NaOH (5.2 ml of a 1N solution) in 15ml methanol was stirred for 30 minutes at 25° C., cooled to 0°-5° C.,acidified, diluted with water and extracted with ethyl acetate. Theorganic layers were washed with brine and dried (MgSO₄). Removal of thevolatiles in vacuo provided 1.28 g of the solid product which was usedwithout further purification.

Step 7: Preparation of trans-(E)-6-[2-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]ethenyl]-3.4.5.6-tetrahydro-4-hydroxy-2H-pyran-2-one

To a solution of7-[3-(4-fluorophenyl)bicyclo[3.2.1]-oct-2-en-2-yl]-3,5-dihydroxyhept-6-enoicacid (1.28 g, 3.55 mmoles) in 15 ml anhydrous ether at 0°-5° C. wasadded dicyclohexylcarbodiimide (0.74 g, 3.55 mmoles). The mixture wasstirred for 4 hours, filtered and the volatiles were removed in vacuo.Purification of the residue using silica gel and 60% hexanes in ethylacetate as the eluent provided 0.518 g of the solid product. mp123°-127° C.

EXAMPLE 2 Step 1: Preparation of3-(4-fluorobenzylidene)bicyclo[2.2.2]oct-5-en-2-one

A solution of bicyclo[2.2.2]oct-5-en-2-one (J. Org. Chem. 33, 2211(1968)) (3.34 g, 27.4 mmoles), 4-fluorobenzaldehyde (3.08 ml, 28.7mmoles) and KOH (2 pellets) in 10 ml of 2-propanol was heated at 60° C.for 1.5 hours, cooled to room temperature and diluted with H₂ O andether. The organic layer was washed with H₂ O, 2% aqueous HCl, saturatedNaHCO₃ and brine and dried (MgSO₄). Removal of the volatiles in vacuoprovided a residue which was recrystallized with hexanes. mp 85°-86° C.

Step 2: Preparation ofexo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-one

A mixture of 3-(4-fluorobenzylidine)bicyclo[2.2.2]oct5-en-2-one (1.68 g,7.37 mmoles), zinc dust (4.79 g, 73.7 mmoles) and glacial acetic acid(4.2 ml, 73.7 mmoles) in 35 ml anhydrous tetrahydrofuran (THF) wasstirred at ambient temperature for 4 hours and filtered through celite.The filtrate was concentrated in vacuo. The residue was diluted withethyl acetate, washed with H₂ O, saturated NaHCO₃ and brine and dried(MgSO₄). Removal of the volatiles in vacuo provided a residue which waspurified by silica gel chromatography using 10% ethyl acetate in hexanesas the eluent. Concentration in vacuo of the product rich fractionsprovided the product (l.33g) as an oil.

Step 3: Preparation ofexo-3-(4-fluorophenylmethyl)-2-(3methoxy-2-propenylidene)bicyclo(2.2.2]oct-5-ene

To a solution of 3-methoxy-2-propenyltriphenylphosphonium bromide (5.59g, 13.6 mmoles) in 50 ml anhydrous THF at -40° C. was added dropwisen-butyl lithium (5.43 ml of a 2.5M solution in hexanes, 13.6 mmoles).The solution was stirred 1.5 hours andexo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-one (2.08 g, 9.04mmoles) in 20 ml anhydrous THF was added dropwise. The mixture wasslowly warmed to ambient temperature, stirred overnight, and dilutedwith ether and aqueous HCl. The organic layer was washed with H₂ O,saturated NaHCO₃ and brine and dried (MgSO₄). Removal of the volatilesin vacuo provided a residue which was purified by HPLC using 2% ethylacetate in hexanes as the eluent. Concentration in vacuo of the productrich fractions provided 1.14 g of the oily product as a mixture of (E)-and (Z)-isomers.

Step 4: Preparation of (E)-3-[cis-exo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5 -en-2-yl]propenal

A solution of exo-3-(4-fluorophenylmethyl)-2-(3-methoxy-2-propenylidene)bicyclo[2.2.2]oct-5-ene (1.4 g) in 25 ml THF and 3 ml of 4N HCl wasstirred for 5 days and the volatiles were removed in vacuo. The residuewas diluted with ether, washed with H₂ O, saturated NaHCO₃ and brine anddried (MgSO₄). Removal of the volatiles in vacuo provided a residuewhich was purified by silica gel chromatography using 5% ethyl acetatein hexanes as the eluent. Concentration in vacuo of the product richfractions provided 0.60 g of the oily product.

Step 5: Preparation of methyl(E)-7-(cis-exo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-yl]-5-hydroxy-3-oxohept-6-enoate

To a slurry of pentane-washed NaH (94 mg of 60%, 2.34 mmoles) in 1.5 mlanhydrous THF at 0°-5° C. was added dropwise methyl acetoacetate (0.21ml, 1.95 mmoles). The solution was stirred for 30 minutes and n-butyllithium (0.82 ml of a 2.5M solution in hexanes, 2.0 mmoles) was addeddropwise. The solution was stirred for 15 minutes and a solution of(E)-3-[cis-exo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-yl]propenal(0.58 g, 2.15 mmoles) in 5 ml anhydrous THF was added. The solution wasstirred for 90 minutes and quenched with 4N HCl and ether. The organiclayer was washed with H₂ O, saturated NaHCO₃ and brine and dried(MgSO₄). Removal of the volatiles in vacuo provided a residue which waspurified by silica gel chromatography using 25% ethyl acetate inhexanes. Concentration in vacuo of the product rich fractions provided0.23 g of the oily product.

Step 6: Preparation of methyl(E)-7-[cis-exo-3-(4-fluorohenylmethyl)bicyclo[2.2.2]oct-5-en-2-yl]-3,5-dihydroxyhept-6-enoate A solution of methyl(E)-7-[cis-exo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-yl]-5-hydroxy-3-oxohept-6-enoate (0.22 g, 0.57 mmoles)and triethylborane (0.85 ml of 1M THF solution, 0.85 mmoles) was stirredfor 10 minutes and cooled to -78° C. and NaBH₄ (32 mg, 0.85 mmoles) wasadded, followed by the dropwise addition of methanol (0.4 ml) over 5minutes. The solution was stirred for 30 minutes, quenched with H₂ O₂(1.0 ml of 30% in 2.5 ml H₂ O), warmed to ambient temperature andstirred for 30 minutes. The solution was diluted with ethyl acetate andaqueous HCl. The organic layer was washed with H₂ O and brine and dried(MgSO₄). Removal of the volatiles in vacuo provided a residue which waspurified by silica gel chromatography using 50% ethyl acetate in hexanesas the eluent. Concentration in vacuo of the product rich fractionsprovided 0.18 g of the oily product. Step 7: Preparation oftrans-(E)-6-[2-[cis-exo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-yl]ethenyl]-3,4,5,6tetrahydro-4-hydroxy-2H-pyran-2-one

To a solution of methyl (E)-7-[cis-exo-3-(4-fluorophenylmethyl)bicyclo[2.2.2]oct-5-en-2-yl]-3,5-dihydroxyhept6-enoate (0 15 g) in 3 mlmethanol at 0°-5° C. was added 0.2 ml of 2N NaOH. The solution wasstirred for 6 hours and the volatiles were removed in vacuo. The residuewas diluted with water, acidified to pH 2 and extracted with ethylacetate. The organic extracts were combined, washed with brine and dried(MgSO₄). Removal of the volatiles in vacuo provided a residue which wasdiluted with 4 ml CHCl₃. The solution was heated at reflux for 16 hoursand the volatiles were removed in vacuo. Purification of the residue bysilica gel chromatography using 33% ethyl acetate in hexanes as theeluent provided the product. mp 144°-146° C.

Employing the general methods detailed in Examples 1 and 2 the followingcompounds can be made:

trans-(E)-6-[2-[3-(4-fluoro-3-methylphenyl)-1,5,8,8-tetramethylbicyclo[3.2.1]oct-2-en-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-(E)-6-[2-[3-(4-fluoro-3-chlorophenyl)-1,5-di-(1methylethyl)bicyclo[3.2.1]oct-2-en-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-6-[2-[cis-endo-3-(4-methylphenyl)bicyclo[3.2.1]octan2-yl]ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-(E)-6-[2-[3-(4-fluoro-3-methylphenyl)-1,5-dimethylbicyclo3.2.1]octa-2,6-dien-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

(E)-7-[3-(4-trifluoromethylphenyl)-1,5-dimethylbicyclo-[3.2.2]non-2-en-2-yl]-3,5-dihydroxyhept-6-enoicacid sodium salt;

(E)-7-[3-(4-fluorophenylmethyl)bicyclo[3.2.2]non-2-en-2-yl]-3,5-dihydroxyhept-6-enoic acid sodium salt;

trans-(E)-6-[2-[cis-exo-3-(4-fluoro-3-methylphenyl)bicyclo[2.2.2]oct-5-en-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-(E)-6-[2-[3-(4-fluoro-3-methylphenyl)-1,4-dimethylbicyclo[2.2.2]octa-2,5-dien-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-(E)-6-[2-[trans-3-(3,4-ditrifluorophenyl)-1,4-di-(1-methylethyl)bicyclo[2.2.2]octan-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-(E)-6-[3-(3-methylphenylmethyl)-1-methylbicyclo[2.2.2]oct-2-en-2-yl]ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;

(E)-7-[3-(4-fluorophenyl)-1,4-dimethylbicyclo[2.2.1]hepta-2,5-dien-2-yl]-3,5-dihydroxyhept-6-enoicacid; and

7-[cis-exo-3-(4-chlorophenylmethyl)-1,4-dimethylbicyclo[2.2.1]heptan-2-yl]-3,5-dihydroxyheptanoicacid.

The compounds of the present invention are useful as hypocholesterolemicor hypolipidemic agents by virtue of their ability to inhibit thebiosynthesis of cholesterol through inhibition of the enzyme HMG-CoAreductase. Having such ability, the compounds are incorporated intopharmaceutically acceptable carriers and administered to a patient inneed of such cholesterol biosynthesis inhibition orally or parenterally.Such pharmaceutical formulations to contain at least one compoundaccording to the invention.

Suitable carriers include diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents. The compositions may be formulatedin the form of tablets, capsules, lozenges, trochees, hard candies,powders, aqueous suspensions, or solutions, injectable solutions,elixirs, syrups and the like and may contain one or more agents selectedfrom the group including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a pharmaceuticallyacceptable preparation.

The particular carrier and the ratio of active compound to carrier aredetermined by the solubility and chemical properties of the compounds,the particular mode of administration and standard pharmaceuticalpractice. For example, excipients such as lactose, sodium citrate,calcium carbonate and dicalcium phosphate and various disintegrants suchas starch, alginic acid and certain complex silicates, together withlubricating agents such as magnesium stearate, sodium lauryl sulphateand talc, can be used in producing tablets. For a capsule form, lactoseand high molecular weight polyethylene glycols are among the preferredpharmaceutically acceptable carriers.

Where aqueous suspensions for oral use are formulated, the carrier canbe emulsifying or suspending agents. Diluents such as ethanol, propyleneglycol, and glycerin and their combinations can be employed as well asother materials.

For parenteral administration, solutions or suspensions of thesecompounds in aqueous alcoholic media or in sesame or peanut oil oraqueous solutions of the soluble pharmaceutically acceptable salves canbe employed.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Doses mayvary, depending on the age, severity, body weight and other conditionsof the patients but are ordinarily in the area of 5 mg/kg to 500 mg/kgof body weight in oral administration; such may, of course be given intwo to four divided doses. With other forms of administration equivalentor adjusted doses will be administered depending on the route ofadministration.

The utility of the claimed compounds is measured by the test methoddescribed hereunder. The method is based on the articles: "Purificationof 3-hydroxy-3-methylglutarylcoenzyme A reductase from rat liver" byKleinsek et al., Proc. Natl. Acad. Sci. USA, Vol. No. 4, pp. 1431-1435,April 1977 Biochemistry; "Mevinolin: A highly potent competitiveinhibitor of hydroxy methyl glutaryl-coenzyme A reductase and acholesterol-lowering agent" by Alberts et al., Proc. Natl. Acad. Sci.USA, Vol 77, pp. 3951-3961, July 1980, Biochemistry; "Effects of ML-236Bon cholesterol metabolism in mice rats: Lack of hypocholesterolemicactivity in normal animals" by Endo et al., Biochimica et BiophysicaActa, 575 (1979) 266-276; and "Evidence of regulation of3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterolsynthesis in nonhepatic tissues of rat" by Balasubramaniam et al., Proc.Natl. Acad. Sci. USA, Vol. 73, No. 8, pp. 2564-2568, Aug. 1976,Biochemistry.

The method used (designated HMGR Screen) was as follows. Male rats wereacclimated to an alternate 12 hour light-dark cycle for a period of 2-3weeks. The animals, weighing 180-230 g, were fed ad libitum a rat chowcontaining 2% cholestyramine for 5 days prior to sacrifice at themid-dark period. Liver microsomes were prepared and HMGR enzyme wassolubilized from the microsomes by freeze-thaw manipulation in highionic strength buffer. The enzyme preparation was stored at -80° C. in300 μl portion samples. Prior to use, the enzyme was activated at 37° C.for 30 minutes in a reaction mixture. The reaction mixture contained ina volume of 240 μl : 0.14 M potassium phosphate buffer (pH 7.0); 0.18 MKCl; 3.5 mM EDTA; 10 mM dithiothreitol; 0.1 mg/ml BSA; 30,000 cpm of [¹⁴C] HMG-CoA; 20 μM HMG-CoA, and 200 μg of solubilized enzyme with andwithout inhibitors (in 10 μl DMSO). After 5 minutes incubation at 37° C.the reaction was initiated with 0.2 mM NADPH. The final assay volume was300 μl. The reaction then was terminated with 100 μl of 1N HCl. After anadditional incubation for 15 minutes at 37° C. to allow for completelactonization of the product, the mixture was diluted with 3 ml GDW. Thediluted mixture was then poured over a 0.7×1.4 cm column containing100-200 mesh Bio-Rex ion-exchange resin (cloride form of Bio-Rad) whichwas equilibrated with distilled water. With this resin the unreacted [¹⁴C] HMG-CoA was adsorbed and the product [¹⁴ C] lactone was eluted (80%recovery) directly into scintillation vials. After the addition of 10 mlof Aquasol®, radioactivities of the samples were measured in ascintillation counter. The compounds tested were found to inhibit theenzyme of HMG-CoA reductase in the range of IC₅₀ =0.5-10 μM and,therefore, can be used for the treatment and prevention ofhypercholesterolemia, hyperlipoproteinemia and arteriosclerosis.

What is claimed is:
 1. Hydroxy acids and pharmaceutically acceptablesalts thereof of a compound of the formula ##STR4## wherein Y is:--CH--, --CHRCHR--, --CHRCHRCHR--, or --RC═CR--;X, X₁ and X₂ areindependently: H, F, Cl, Br, OH, CF₃, alkyl, aryl, NO₂, NH(CO)R, N(R)₂,or S(O)_(n) R; R, R₁, R₂, R₃ and R₄ are independently: H or lower alkyl;m is: 1 or 2; m' is: 0 or 1; m" is: 0 or 1; n=0, 1, 2; and the dottedlines in the bicyclic ring represent optional double bonds.
 2. Acompound of claim 1 wherein x is fluoro and x₁ is lower alkyl.
 3. Acompound of claim 1 wherein x, R₁ and R₂ are alkyl of one to six carbonatoms.
 4. A compound of claim 1 wherein X and X₁ are aryl and X₂ istrifluoromethyl.
 5. A compound of claim 1 wherein at least one of the X,X₁ and X₂ radicals is phenyl.
 6. A compound of claim 1 wherein at leastone of the X, X₁ and X₂ radicals is substituted phenyl.
 7. A compound ofclaim 1 wherein at least one of the X, X₁ and X₂ radicals is naphthyl.8. A compound of claim 1 wherein R is lower alkyl having 1-4 carbonatoms.
 9. A compound of claim 1 wherein R₃ and R₄ are lower alkyl.
 10. Acompound of claim 1 wherein m is 2, m' is 0 and m" is
 1. 11. A compoundof claim 1 wherein m is 1, m' is 1 and m" is
 0. 12. A compound of claim1 wherein Y is --CH═CH--.
 13. A compound of claim 1 wherein Y is --CH₂CH₂ --. 14.(E)-7-[3-(4-trifluoromethylphenyl)-1,5-dimethylbicyclo[3.2.2]non-2-en-2-yl]-3,5-dihydroxyhept-6-enoicacid sodium salt. 15.(E)-7-[3-(4-fluorophenylmethyl)bicyclo[3.2.2]non-2-en-2-yl]-3,5-dihydroxyhept-6-enoicacid sodium salt. 16.(E)-7-[3-(4-fluorophenyl)-1,4-dimethylbicyclo[2.2.1]hepta-2,5-dien-2-yl]-3,5-dihydroxyhept-6-enoic acid. 17.7-[cis-exo-3-(4-chlorophenylmethyl)-1,4-dimethylbicyclo[2.2.1]heptan-2-yl]-3,5-dihydroxyheptanoicacid.
 18. A hypocholesterolemic, hypolipidemic pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 19. A method ofinhibiting cholesterol biosynthesis in a patient in need of suchtreatment comprising administering a pharmaceutical composition definedin claim 1.